7-((3,5,7-triaza-1-azonia-1-adamantyl)-acetamido)-cephalosporanic acid halides and sulfonates

ABSTRACT

NEW 7 - ((3,5,7-TRIAZA-L-AZONIA-1-ADAMANTYL) ACETAMIDO)-CEPHALOSPORANIC ACID HALODES AND SULFONATES OF THE FOLLOWING GENERAL FORMULA   (2-(R-OOC-),3-(X-CH2-),7-((3,5,7-TRIAZA-1-AZANONIA-1-   ADAMANTYL)-C(-R1)(-R2)-CO-NH-)-2-CEPHEM   WHEREIN R IS HYDROGEN, LOWER ALKYL, ARALKYL OR THE GROUP R3-COO-CH2R1 IS HYDROGEN, LOWER ALKYL, CYCLO-LOWER ALKYL, UNSATURATED CYCLO-LOWER ALKYL, ARYL, ARALKYL, ADAMANTYL, CYCLOHEPTATRIENYL OF A HETEROCYCLIC GROUPL R2 IS HYDROGEN OR LOWER ALKYL; R3 IS LOWER ALKYL, ARYL OR ARALKYL; X IS HYDROGEN HYDROXY, LOWER ALKANOLOXY, AROLOXY OR ARALKANOLOXY OR TOGETHER X AND R REPRESENT A BOND LINKING CARBON AND OXYGEN IN A LACTONE RING AND Z IS A HALOGEN OR SULFONATE GROUP; ARE USEFUL AS ANTIBACTERIAL AGENTS.

3,720,669 7-[(3,5,7 TRIAZA-l-AZONTA 1 ADAMANTYL)- ACETAMIDO] CEPHALOSPORANIC ACID HA- LIDES AND SULFONATES Hermann Breuer, Burgweinting, Germany, assignor to E. R. Squibb & Sons, Princeton, NJ. No Drawing. Filed June 28, 1971, Ser. No. 157,690 Int. Cl. C07d 99/24 US. Cl. 260-243 C 6 Claims ABSTRACT OF THE DISCLOSURE New 7 [(3,5,7 triaza-l-azonia-l-adamantyl)acetamido]-cephalosporanic acid halides and sulfonates of the following general formula N) t. am z- JJOOR wherein R is hydrogen, lower alkyl, aralkyl or the group R is hydrogen, lower alkyl, cyclo-lower alkyl, unsaturated cyclo-lower alkyl, aryl, aralkyl, adamantyl, cycloheptatrienyl or a heterocyclic group; R is hydrogen or lower alkyl; R, is lower alkyl, aryl or aralkyl; X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy or aralkanoyloxy or together X and R represent a bond linking carbon and oxygen in a lactone ring and Z is a halogen or sulfonate group; are useful as antibacterial agents.

SUMMARY OF THE INVENTION This invention relates to new antibacterial 7-[(3,5,7- triaza l-azonia-l-adamantyl)acetamido]cephalosporanic acid halides and sulfonates of the formula R represents hydrogen, lower alkyl, aralkyl or the group R represents hydrogen, lower alkyl, cycloalkyl, unsaturated cycloalkyl, aryl, aralkyl, l-adamantyl, 2,4,6-cycloheptatrienyl or a heterocyclic group; R is hydrogen or lower alkyl; R represents lower alkyl, aryl or aralkyl; X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy or aralkanoyloxy. In addition X and R may represent a bond linking carbon and oxygen in a lactone ring. Z is one of the halides chlorine, bromine or iodine or the sulfonate group -OSO R wherein R is lower alkyl, phenyl or tolyl.

The preferred members within each group are as follows: R is hydrogen, lower alkyl, especially hydrogen, methyl, pivaloyloxy, R is hydrogen or phenyl; R is nitcd States Patent "ice hydrogen; R is lower alkyl, preferably methyl or t-butyl; X is hydrogen or acetoxy and Z is bromine, chlorine or iodine (preferably the first two).

DETAILED DESCRIPTION OF THE INVENTION The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.

The lower alkyl groups are straight or branched chain hydrocarbon radicals having one to eight carbons in the chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.

Cycloalkyl groups include cycloaliphatic groups having three to seven carbons in the ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cyclic groups may also be cycloalkenyl and cycloalkadienyl groups of the same type, e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, etc. The 2,4,6-cycloheptatrienyl group is also included. The double bond or bonds may be variously located. A particularly preferred radical in this group is the 1,4-cyclohexadienyl group. These may be simply substituted with one to three groups such as halogen, lower alkyl or lower alkoxy.

The aryl groups are monocyclic carbocyclic aryl groups including simply substituted members. By way of illustration, this includes the phenyl ring and simply substituted phenyl containing one to three substituents (preferably only one) such as the halogens (chlorine and bromine being preferred), lower alkyl groups such as those defined above, lower alkoxy groups, (i.e., lower alkyl groups of the type defined above attached to an oxygen), hydroxy, lower alkanoyl or lower alkanoyloxy. Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mand p-bromophenyl, 3,4-dichlor0phenyl, 3,5-dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl and p-hydroxyphenyl.

The aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. Illustrative or benzyl, o-, mor p-chlo'robenzyl, o, mor p-bromobenzyl, o-, mor p-methylbenzyl, phenethyl, p-chlorophenethyl, 3,5-diethylbenzyl, 3,4,5-trichlorobenzyl and the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters. The lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above. The lower alkanoylo-xy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like. the aroyloxy groups are derived from monocyclic carbocyclic aryl groups of the kind described. Similarly the aralkanoyloxy groups consist of monocyclic carbocyclic aryl and alkanoyloxy radicals of the type described. X and R may also join together, as indicated above to form a bond linking carbon and oxygen in a lactone ring.

The heterocyclic groups represented by R, are 5- to 6mem-bered monocyclic heterocyclic radicals (exclusive of hydrogen) containing nitrogen, sulfur or oxygen in the ring in addition to carbon (not more than two hetero atoms), and simply substituted members of this group as discussed above with respect to the aryl groups. The heterocyclic radicals include, for example, pyridyl, pyrrolidyl, morpholinyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and the like, as well as the simply substituted members, especially the halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy), phenyl and hydroxy-lower alkyl (particularly hydroxymethyl and hydroxyethyl) substituted members.

Z is one of the halides chlorine, bromine or iodine, or a sulfonate radical derived from a lower alkylsulfona'te such as methanesulfonate or benzenesulfonate or toluenesulfonate.

The compounds of Formula I are produced by reacting a compound of the formula with hexamethylenetetramine in an inert organic solvent, chloroform being preferred at about room temperature or below, e.g., about 10 to 25.

When R is the acyloxymethyl group this group may be introduced onto the 7-aminocephalosporanic acid or 7-aminodesacetoxycephalosporanic acid moiety either prior to or subsequent to the reaction with the hexamethylenetetramine by treatment with one to two moles of a halomethyl ester of the formula (III) hal-CH OCOR wherein hal is hydrogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like at about ambient temperature or below.

It will be appreciated that certain of the compounds of this invention exist in various states of solvation as well as in different isomeric or optically active forms. The various forms as well as their mixtures are within the scope of this invention.

Further process details are provided in the illustrative examples.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of Formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./ kg. in mice.

Oral forms give prompt high blood levels which are maintained for relatively long periods.

Up to about 600 mg. of a compound of Formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of about 0.1 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying.

They are also useful as nutritional supplements in animal feeds.

4 The following examples are illustrative of the invention. All temperatures are on the centigrade scale. Additional variations may be produced in the same manner by appropriate substitution in the starting material.

EXAMPLE 1 7-[3,5,7-triaza-1-azonia-l-adamantyl)acetamido] cephalosporanic acid brodime 0.78 gm. (0.002 mol.) of 7-(2-bromoacetamido)cephalosporanic acid (produced from bromacetyl chloride and 7-aminocephalosporanic acid) are dissolved in 16 ml.

:of chloroform. 0.42 gm. (0.003 mol.) of hexamethylenetetramine are added. The clear solution is stirred overnight at a temperature of 1'0-l5. The mixture is filtered to remove a slight turbidity and the product is precipitated by the addition of ether. The product, 7-[3,5,7-triaza-1- azonia-l-adamantyl)acetamido]cephalosporanic acid bromide, melts at C. (with dec.), yield 1.3 g.

EXAMPLE 2 7- [2-(3,5,7-triaza-1-azonia-1-adamantyl)-2-phenylacetamido1cephalosporanic acid bromide 0.94 g. (0.002 mol.) of 7-(2-bromo-2-phenylacetamido)cephalosporanic acid (produced from 2-bromo-2-phenacetyl bromide and 7-aminocephalosporanic acid and 0.42 g. (0.003 mol.) of hexamethylenetetramine are dissolved in anhydrous chloroform and the clear solution is stirred overnight at a temperature of 10-15. The solution is filtered to remove the turbidity. The addition of ether precipitates the product, 7-[2-(3,5,7-triaza-1-azonia-l-adarnantyl)-2-phenylacetamido]cephalosporanic acid bromide, M.P. 147 (with dec.), yield 1.2 g.

EXAMPLE 3 7-[2-(3,5,7-triaza-l-azonia-l-adamantyl)-2phenylacetamido]cephalosporanic acid chloride By substituting 7-(2-chloro-2-phenylacetamido)cephalosporanic acid for its 2-brorno analog in the procedure of Example 2, 7-[2-(3,5,7-triaza-l-azonia-l-adamantyl)- 2-phenylacetamido]cephalosporanic acid chloride is obtained.

EXAMPLE 4 7- 3,5 ,7 -triazal-azonia-l-adamantyl) acetamido] cepha'osporanic acid iodide By substituting 7-(2-iodoacetamido)cephalosporanic acid (prepared from iodoacetyl chloride and 7-aminocephalosporanic acid) for its 2-bromo analog in the procedure of Example 1, 7-[3,5,7-triaza-1-azonia-l-adamantyl) acetamido]cephalosporanic acid iodide is obtained.

EXAMPLE 5 7-[2-(3,5,7-triaza-l-azonia 1 adamantyl) 2 phenylacetamido]-3-desacetoxycephalosporanic acid methyl ester bromide 7 EXAMPLE 34 The sterile powders are aseptically blended and filled into sterile vials, and sealed. The addition of 1 ml. of water for injection to the vial provides a suspension for intramuscular injection.

What is claimed is:

1. A compound of the formula wherein R is hydrogen, lower alkyl, aralkyl or R is hydrogen, lower alkyl, a cycloaliphatic group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, cycloheptatrienyl and said cycloaliphatics bearing chlorine, bromine, lower alkyl or lower alkoxy, aryl,

aralkyl, adamantyl, heterocyclic selected from the group consisting of pyridyl, pyrrolidyl, morpholinyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl or said heterocyclic bearing chlorine, bromine, lower alkyl, lower alkoxy, phenyl or hydroxy-lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl, aryl or arylalkyl; X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy or together X and R represent a bond linking carbon and oxygen in a lactone ring; Z is chlorine, bromine, iodine or OSO R wherein R is lower alkyl, phenyl or tolyl; said aryl, aralkyl, aroyloxy and aralkanoyloxy being, respectively, phenyl, phenyl-lower alkyl, phenoxy and phenyl-lower alkanoyloxy and said groups bearing on the phenyl chlorine, bromine, lower alkyl, lower alkoxy, hydroxy, lower alkanoyl or lower alkanoyloxy.

2. A compound as in claim 7 wherein R is hydrogen, lower alkyl or pivaloyloxy; R is hydrogen or phenyl; R is hydrogen; R is lower alkyl; X is hydrogen or acetoxy and Z is bromine or chlorine.

3. A compound as in claim 1 wherein R, R and R each is hydrogen, X is acetoxy and Z is bromine.

4. A compound as in claim 1 wherein R, R R and X each is hydrogen and Z is bromine.

5. A compound as in claim 1 wherein R and R each is hydrogen, R is phenyl, X is acetoxy and Z is bromine.

6. A compound as in claim 1 wherein R, R and X each is hydrogen, R is phenyl and Z is bromine.

References Cited UNITED STATES PATENTS 3,468,874 9/1969 Raap et al. 260243 C NICHOLAS S. RIZZO, Primary Examiner U.S. Cl. X.R. 

